CA2632272A1 - Sulfamoyl sulfonate prodrugs - Google Patents
Sulfamoyl sulfonate prodrugs Download PDFInfo
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- CA2632272A1 CA2632272A1 CA002632272A CA2632272A CA2632272A1 CA 2632272 A1 CA2632272 A1 CA 2632272A1 CA 002632272 A CA002632272 A CA 002632272A CA 2632272 A CA2632272 A CA 2632272A CA 2632272 A1 CA2632272 A1 CA 2632272A1
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- quinine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
- C07J41/0072—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the A ring of the steroid being aromatic
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/26—Androgens
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/30—Oestrogens
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
- C07J41/0038—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 with an androstane skeleton, including 18- or 19-substituted derivatives, 18-nor derivatives and also derivatives where position 17-beta is substituted by a carbon atom not directly bonded to a further carbon atom and not being part of an amide group
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Abstract
The invention relates to the sulfamoyl sulfonate prodrugs of general formula (I), to a method for producing them, to pharmaceutical compositions containing the same and to their use for producing orally available drugs. The compounds according to the invention bind to carboanhydrases and inhibit these enzymes.
Description
Sulfamoyl Sulfonate Prodrugs The invention relates to sulfamoyl sulfonate prodrugs of general formula I, //O
X ~=0 js~ NH 2 p ~\
O
Drug ; Gruppe Z
[Group Z] (I), a process for the production of these prodrugs, pharmaceutical compositions that contain these compounds, and their use for the production of orally available pharmaceutical agents.
From WO 01/91797, steroidal compounds that are bonded via an -S02NR1R2 group to erythrocytes and that accumulate there are known. The concentration ratio of the compounds between erythrocytes and plasma is 10-1000:1, preferably 30-1000:1, so that a depot formation in the erythrocytes can be mentioned. Because of the strong binding of the compounds to the erythrocytes, metabolization is avoided during passage through the liver.
Disadvantageously, no therapy-relevant active ingredient levels are given despite a reduced metabolization with the indicated dosages. Reasons for this can be sought in excessive binding to erythrocytes, an enzyme-induced cleavage and in low solubilities.
It is the object of the invention to provide new prodrugs that are orally available and that, in comparison to the prior art, ensure a therapy-relevant active ingredient level even at a low dosage.
This object is achieved by sulfamoyl sulfonate prodrugs of general formula (I), in which a sulfamoyl radical is bonded to the drug that is to be released via a spacer X by means of a sulfonate bond.
X ~=0 js~ NH 2 p ~\
O
Drug ; Gruppe Z
[Group Z] (I), a process for the production of these prodrugs, pharmaceutical compositions that contain these compounds, and their use for the production of orally available pharmaceutical agents.
From WO 01/91797, steroidal compounds that are bonded via an -S02NR1R2 group to erythrocytes and that accumulate there are known. The concentration ratio of the compounds between erythrocytes and plasma is 10-1000:1, preferably 30-1000:1, so that a depot formation in the erythrocytes can be mentioned. Because of the strong binding of the compounds to the erythrocytes, metabolization is avoided during passage through the liver.
Disadvantageously, no therapy-relevant active ingredient levels are given despite a reduced metabolization with the indicated dosages. Reasons for this can be sought in excessive binding to erythrocytes, an enzyme-induced cleavage and in low solubilities.
It is the object of the invention to provide new prodrugs that are orally available and that, in comparison to the prior art, ensure a therapy-relevant active ingredient level even at a low dosage.
This object is achieved by sulfamoyl sulfonate prodrugs of general formula (I), in which a sulfamoyl radical is bonded to the drug that is to be released via a spacer X by means of a sulfonate bond.
Sulfamoyl sulfonate prodrugs of general formula (I) are X S=0 S NHZ
p~ \0 Drug Gruppe Z
[Group Z] (I), in which X is a C1_12-alkanediyl-, a CPFZp group where p= 1-5, a C3_g-cycloalkanediyl-, an arylene-, a heteroalkanediyl-, a C1.4-alkanediylaryl-, a C1_4-alkanediyl-C3_8-cycloalkyl- or a C3_8-cycloalkanediyl-C1_4-alkyl group, and Drug is a pharmaceutical active ingredient that can form a sulfonate via an OH
group, such as steroids, anti-malaria agents, nucleosides, or isoflavonoids, which can optionally be substituted.
The sulfamoyl sulfonate compounds according to the invention bond to erythrocytes, are readily water-soluble and are hydrolytically cleaved without assistance from enzymes.
For the purpose of this invention, "C1_12-alkanediyl group" is defined as a double-bonded, branched or straight-chain alkylene radical with up to 12 carbon atoms that optionally can be substituted with, e.g., halogen atoms, hydroxy groups, or nitrile groups. As examples, a methane-l,l-diyl-, ethane-1,2-diyl, propane-1,3-diyl-, butane-l,4-diyl-, pentane-1,5-diyl-; hexane-1,6-diyl-, octane-l,8-diyl-, and undecane-1,11-diyl group can be mentioned.
For the purpose of this invention, CPF2P group with p = 1-5 is defined as a branched or straight-chain perfluorinated alkyl radical with up to 5 carbon atoms. As examples, a perfluoropropane-1,3-diyl-, perfluorobutane-1,4-diyl-, and perfluoropentarie-1,5-diyl group can be mentioned.
The above-mentioned "C3_8-cycloalkanediyl group" means, according to the invention, a double-bonded, mono- or bicyclic, carbocyclic group with 3 to 8 carbon atoms that optionally can be substituted with halogen atoms, hydroxy groups, and nitrile groups, such as, for example, with a cyclobutane-1,3-diyl-, cyclopentane-1,3-diyl- or a cyclohexane-1,4-diyl group.
The above-mentioned "arylene group" means, according to the invention, a double-bonded, aromatic mono- to tricyclic, carbocyclic group with 6 to 15 carbon atoms that optionally can be substituted with halogen atoms, hydroxy groups, nitrile groups, and alkyl groups, such as, for example, with an m-phenylene-, p-phenylene-, phenanthrylene- or a naphthalene group.
The heteroarylene radical includes, in each case, 5-16 ring atoms and contains, instead of carbon, one or more heteroatoms that are the same or different, such as oxygen, nitrogen or sulfur, in the ring. The heteroaryl radical can be mono-, bi- or tricyclic.
For example, there can be mentioned: thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, benzofuranyl, benzothienyl, benzothiazole, benzoxazolyl, benzimidazolyl, indazolyl, indolyl, isoindolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolyl, and isoquinolyl.
For the purpose of the invention, a heteroalkanediyl group is a double-bonded, straight-chain or branched, saturated or unsaturated heteroalkyl radical with, in each case, 1-6 carbon atoms and can contain, instead of carbon, one or more heteroatoms that are the same or different, such as oxygen, nitrogen or sulfur, such as, for example, a bis-ethylenoxy radical.
p~ \0 Drug Gruppe Z
[Group Z] (I), in which X is a C1_12-alkanediyl-, a CPFZp group where p= 1-5, a C3_g-cycloalkanediyl-, an arylene-, a heteroalkanediyl-, a C1.4-alkanediylaryl-, a C1_4-alkanediyl-C3_8-cycloalkyl- or a C3_8-cycloalkanediyl-C1_4-alkyl group, and Drug is a pharmaceutical active ingredient that can form a sulfonate via an OH
group, such as steroids, anti-malaria agents, nucleosides, or isoflavonoids, which can optionally be substituted.
The sulfamoyl sulfonate compounds according to the invention bond to erythrocytes, are readily water-soluble and are hydrolytically cleaved without assistance from enzymes.
For the purpose of this invention, "C1_12-alkanediyl group" is defined as a double-bonded, branched or straight-chain alkylene radical with up to 12 carbon atoms that optionally can be substituted with, e.g., halogen atoms, hydroxy groups, or nitrile groups. As examples, a methane-l,l-diyl-, ethane-1,2-diyl, propane-1,3-diyl-, butane-l,4-diyl-, pentane-1,5-diyl-; hexane-1,6-diyl-, octane-l,8-diyl-, and undecane-1,11-diyl group can be mentioned.
For the purpose of this invention, CPF2P group with p = 1-5 is defined as a branched or straight-chain perfluorinated alkyl radical with up to 5 carbon atoms. As examples, a perfluoropropane-1,3-diyl-, perfluorobutane-1,4-diyl-, and perfluoropentarie-1,5-diyl group can be mentioned.
The above-mentioned "C3_8-cycloalkanediyl group" means, according to the invention, a double-bonded, mono- or bicyclic, carbocyclic group with 3 to 8 carbon atoms that optionally can be substituted with halogen atoms, hydroxy groups, and nitrile groups, such as, for example, with a cyclobutane-1,3-diyl-, cyclopentane-1,3-diyl- or a cyclohexane-1,4-diyl group.
The above-mentioned "arylene group" means, according to the invention, a double-bonded, aromatic mono- to tricyclic, carbocyclic group with 6 to 15 carbon atoms that optionally can be substituted with halogen atoms, hydroxy groups, nitrile groups, and alkyl groups, such as, for example, with an m-phenylene-, p-phenylene-, phenanthrylene- or a naphthalene group.
The heteroarylene radical includes, in each case, 5-16 ring atoms and contains, instead of carbon, one or more heteroatoms that are the same or different, such as oxygen, nitrogen or sulfur, in the ring. The heteroaryl radical can be mono-, bi- or tricyclic.
For example, there can be mentioned: thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, benzofuranyl, benzothienyl, benzothiazole, benzoxazolyl, benzimidazolyl, indazolyl, indolyl, isoindolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolyl, and isoquinolyl.
For the purpose of the invention, a heteroalkanediyl group is a double-bonded, straight-chain or branched, saturated or unsaturated heteroalkyl radical with, in each case, 1-6 carbon atoms and can contain, instead of carbon, one or more heteroatoms that are the same or different, such as oxygen, nitrogen or sulfur, such as, for example, a bis-ethylenoxy radical.
The "C14-arylalkanediyl group" is an aryl group that is bonded to a skeleton via a C1 C4-alkanediyl group, whereby the alkanediyl group can be straight-chain or branched. For example, benzyl or phenethylene can be mentioned.
The "C3_8-cycloalkyl-C1_4-alkanediyl group" means, for example, cycloalkyl-(CH2)-, cycloalkyl-(C2H4)-, cycloalkyl-(C3H6)-, cycloalkyl-(C4Hg)-, or cycloalkyl-(C5H,o)-. In this case, cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.
"C1_4-Alkyl-C3_8-cycloalkanediyl group" is defined as methylcycloalkanediyl, ethyl-cycloalkanediyl, propylcycloalkanediyl, butylcycloalkanediyl, or pentylcycloalkanediyl. In this case, cycloalkanediyl can be cyclopropane-1,3-diyl, cyclobutane-1,4-diyl, cyclopentane-1,5-diyl, cyclohexane-1,6-diyl, cycloheptane-1,7-diyl or cyclooctane-1,8-diyl.
In the context of this invention, the term "halogen atom" is defined as a fluorine, chlorine, bromine or iodine atom, preferably a fluorine, chlorine, or bromine atom.
A pharmaceutical active ingredient that can form a sulfonate via an OH group means, for the purpose of the invention, the following:
Steroids: Estrogens, for example estradiol or estriol, or androgens, for example testosterone, MENT (7 a-methyl-19-nortestosterone), eF-MENT (11 -fluoro-7 a-methyl-l9-nortestosterone), nandrolone, DHT (dihydrotestosterone), or gestagens, for example norethisterone, dienogest or levonorgestrel, or corticoids, for example cortisol Anti-malaria agents: quinine, cinchonidine, hydroxychloroquine, primaquine, mefloquine;
or Nucleosides: consisting of a sugar, such as ribose or deoxyribose, and a base, such as adenine, guanine, cytosine, thymine or uracil, and also zidovudine, brivudine, indinavir, and nelfinavir;
Isoflavonoids: genisteine.
Especially preferred compounds are specified as follows:
1) 3-hydroxyestra-1,3,5(10)-trien-17(3-y13'-sulfamoylphenyl sulfonate, 2) 3-acetoxyestra-1,3,5(10)-trien-17(3-yl 3'- sulfamoylphenyl sulfonate, 3) 3-tert-butyldimethylsilyloxyestra-1,3,5(10)-trien-170-yl 3'-sulfamoylphenyl sulfonate, 4) 3-hydroxyestra-1,3,5(10)-trien-l7R-y14'-sulfamoylphenyl sulfonate, 5) 2-methoxy-3-hydroxyestra-1,3,5(10)-trien-170-yl 3'-sulfamoylphenyl sulfonate, 6) 3,16a-dihydroxyestra-1,3,5(10)-trien-17(3-yl 3'-sulfamoylphenyl sulfonate, 7) 3,170 -dihydroxyestra-1,3,5(10)-trien-16a-y13'-sulfamoylphenyl sulfonate, 8) 3-benzoyloxyestra-1,3,5(10)-trien-170-yl 3'-sulfamoylphenyl sulfonate, 9) quinine-3'-sulfamoylphenyl sulfonate, 10) cinchonidine-3'-sulfamoylphenyl sulfonate, 11) zidovudine-3'-sulfamoylphenyl sulfonate, 12) 3-oxoandrost-4-en-170-yl 3'-sulfamoylphenyl sulfonate, 13) 3-oxoandrostan-17P-yl 3'-sulfamoylphenyl sulfonate, 14) 3-oxo-7a-methylandrost-4-en-170-yl 3'-sulfamoylphenyl sulfonate, 15) 3-oxoestr-4-en-17(3-yl 3'-sulfamoylphenyl sulfonate, and 16) brivudine-3'-sulfamoylphenyl sulfonate.
The therapeutically relevant drug compound is released through hydrolysis from the compounds according to the invention.
In-Vitro Tests:
Carbonic Anhydrase Inhibition Test Principle:
Photometric determination of the inhibition of human carbonic anhydrase I or II with sulfonamides or sulfamates on microtiter plates with the aid of enzymatic conversion of nitrophenyl acetate with a color change from colorless to yellow.
Table 1: IC50 Inhibiting Values of Human Carbonic Anhydrase I
CAII CAI
Inhibitor IC50 (nM) IC50 (nM) Estradiol-3-sulfamat 34 157 10.6 3-Oxoandrost-4-en-17R-yI 120 2300 3'-aminosulfonylphenyl-sulfonat 3-Oxo-7a-methylandrost-4- 120 2300 en-170-yi 3'-aminosulfonyl-hen Isulfonat 3-Hydroxyestra-1,3,5(10)- 81 1700 trien-17p-yl 3'-aminosulfo-n I hen Isulfonat Zidovudinsulfonat 1100 2900 Acetazolamid 61 1200 bekannter CA-Hemmer) 190 Literature: 1) C. Landolfi, M. Marchetti, G. Ciocci, and C. Milanese, Journal of Pharmacological and Toxicological Methods 38, 169-172 (1997).
[Key to Table 1:]
Estradiol-3-sulfamat = Estradiol-3-sulfamate 3-Oxoandrost-4-en-17R-yl 3'-aminosulfamoylphenylsulfonat = 3-Oxoandrost-4-en-170-yl 3'-sulfamoylphenyl sulfonate 3 -Oxo-7a-methylandrost-4-en-17 0-yl 3'-aminosulfamoylphenylsulfonat = 3 -Oxo-7a-methylandrost-4-en-17(3-yl 3'-aminosulfamoylphenyl sulfonate 3-Hydroxyestra-1,3,5(10)-trien-17(3-yl 3'-aminosulfonylphenylsulfonat = 3-Hydroxyestra-1,3,5(10)-trien-l7R-yl 3'-aminosulfonylphenyl sulfonate Zidovudinsulfonat = Zidovudine Sulfonate Acetazolamid (bekannter CA-Hemmer) = Acetazolamide (Known CA Inhibitor) It was found that the sulfamoyl sulfonate prodrugs according to the invention surprisingly readily inhibit the carbonic anhydrase II. A concentration of the prodrugs, according to the invention, in the erythrocytes can be deduced from this.
Physicochemical Data Solubility in Water a) Kinetic Measurement:
The compounds according to the invention were measured as 10 mmol DMSO
solution in a 0.01 M phosphate buffer solution at pH 7.4 and 25 C with nephelometry and turbidity.
While in a turbid state, the solution to be tested was added drop by drop to the buffer solution until a precipitate settled.
The precipitate was detected in a dilution series (compounds in a phosphate buffer solution according to the invention) by nephelometry.
b.) Thermodynamic Measurement:
The compounds in solid form according to the invention were added to an excess of an aqueous buffer system of various pH values. It was stirred 24 hours at 25 C. After centrifuging, the solution was examined with HPLC (HPLC: column: Xterra MS C18 2.5 m, 30 x 4.6 mm). Two standard gradient systems were used based on the compounds to be measured:
Acidic gradient: A: water/0.01 % trifluoroacetic acid, B: acetonitrile/0. 0 1 %
trifluoroacetic acid - 0 min 5% B, 0-3 min 65% B, 3-5 min 65% B, 5-6 min 5% B
Alkaline gradient: A: water/0.025% ammonia, B: acetonitrile/0.025% ammonia - 0 min 20% B, 0-3 min 80% B, 3-5 min 80% B, 5-6 min 20% B.
Table 2: Water Solubility Substance Solubility in Water Estradiol-3-sulfamate 0.15 mg/100 ml Testosterone Propionate Insoluble 3-Hydroxyestra-1,3,5(10)-trien-170-y13'- 3 mg/1 sulfamoylphenyl Sulfonate 3-Oxoandrost-4-en-170-yl 3'-sulfamoyl- 5 mg/l phenyl Sulfonate 3-Oxo-7a-methylandrost-4-en-17(3-yl 3'- About 6 mg/1 sulfamoylphenyl Sulfonate The compounds according to the invention show a higher solubility when compared to sulfamate- and carboxylic acid ester prodrugs, which allows for better absorption in the intestine.
Hydrolysis The compounds according to the invention were measured as a DMSO solution in an aqueous buffer of various pH values at 37 C.
The quantification took place through HPLC (HPLC column: Xterra MS C18 2.5 m 4.6 x 30mm). Based on the test substances to be measured, the following gradient system was used for the HPLC:
Acidic gradient: A: water/0.01 % trifluoroacetic acid, B: acetonitrile/0. 0 1 %
trifluoroacetic acid - 0 min 5% B, 0-3 min 65% B, 3=5 min 65% B, 5-6 min 5% B
Alkaline gradient: A: water/0.025% ammonia, B: acetonitrile/0.025% ammonia - 0 min 20% B, 0-3 min 80% B, 3-5 min 80% B, 5-6 min 20% B. The quantification took' place after 1 and 2 hours and after 24 hours.
Stability in Simulated Gastric Juice:
Solutions of the compounds according to the invention were incubated at 37 C
in simulated gastric juice (aqueous NaCI solution with pepsin, pH- 1.2).
The quantification took place through HPLC (HPLC-column: Xterra MS C18 2.5 m 4.6 x 30mm) using the gradient system:
A: water/0.01 % trifluoroacetic acid, B: acetonitrile/0.01 % trifluoroacetic acid - 0 min 5% B, 0-3 min 65% B, 3-5 min 65% B, 5-6 min 5% B.
The quantification took place after 0.5, 1, 1.5 and 2 hours.
Table 3: Hydrolysis/Stability in Gastric Juice Decomposition in %
pH =1, 37 C pH = 7.4, 37 C
Substance 30 min 1 h 2 h 24 h 1 h 2h. 24 h 3-Hydroxyestra-1,3,5 4 7 14 80 6 13 84 (10)-trien-17(3-yl3'- (pH=1.2) sulfamoyl-phenyl sulfonate 3-Oxoandrost-4-en- 3 6 11 78 6 12 75 17 (3-y13'-sulfamoyl- (pH=1.2) phenyl sulfonate 3-Oxo-7a-methyl- 6 11 71 6 11 70 androst-4-en-17p-yl 3'-sulfamoylphenyl sulfonate 3-Oxoandrost-4-en- 0 0 0 0 0 0 0 17(3-yl n-propionate Carboxylic acid esters are relatively stable in gastric juice (pH - 1) and in the intestine (pH - 7.4), but are cleaved when passing through the intestine by esterases that exist there. During passage through the stomach, however, the stable prodrug remains almost complete.
The cleavage of the carboxylic acid ester thus takes place when passing through the intestine and in the liver.
No enzymes (esterases) are known for sulfonic acid ester. It was therefore surprising that the sulfonates are still cleaved, whereby a simple hydrolysis takes place. Although a slow hydrolysis already takes place in the gastric juice and when the pH = 7.4, the sulfonates have adequate stability to pass through the stomach and the intestine. An esterase cleavage does not take place in the intestine wall. The first-pass effect in the liver is avoided since the sulfonates are bonded with the sulfonamide group to the erythrocytes.
The compounds of general formula (I) according to the invention can, as a function of the meaning of "drug," be used for the treatment and/or prophylaxis of various clinical pictures. For example, the compounds of general formula (I) can be used if the "drug" is a steroid, such as androgen or estrogen, in hormone replacement therapy (HRT) in women and men, or in the treatment of hormonally-induced diseases in men (prostrate cancer, breast cancer, hypogonadism) and in women (endometriosis, breast cancer). In addition, the compounds of general formula (I) according to the invention, in which "drug,"
for example, stands for an androgen or estrogen, can he used for birth control in men and women.
The use of additional active ingredients mentioned for "drug," such as quinine, cinchonidine, hydroxychloroquine, primaquine or mefloquine, relates to the treatment of malaria.
Compounds of general formula (I) according to the invention, in which "drug"
means a cortisol derivative, can be used for the treatment and prophylaxis of inflammatory and/or allergic diseases that are influenced by immunosuppressive agents and/or antiproliferative agents.
Prodrugs according to the invention, in which "drug" means a nucleoside (zidovudine, brivudine, indinavir, nelfinavir), can be used for the treatment of viral diseases (herpes, HIV).
In addition, subjects of the invention are the pharmaceutical compositions that contain the compounds of general formula (I) according to the invention and optionally additional active ingredients, for example gestagens (norethisterone, dienogest, drospirenone, levonorgestrel), antigestagens (mifepristone, onapristone) and/or progesterone receptor modulators (mesoprogestins, such as asoprisnil).
These pharmaceutical compositions and pharmaceutical agents are preferably administered orally. In addition to the usual vehicles and/or diluents, they contain at least one compound of general formula I.
Dosage The prodrugs according to the invention can be administered orally.
Generally, satisfactory results are to be expected both for the treatment and/or prophylaxis of the above-mentioned indications or for birth control if the dosage is carried out in such a way that after the administration of the prodrugs, an amount of the corresponding active ingredient ("drug") is released that corresponds to the highest pharmaceutically used maximum dose of the respective "drug" substance.
The pharmaceutical agents of the invention are produced in a known way with the usual solid or liquid vehicles or diluents and the commonly used pharmaceutical-technical adjuvants corresponding to the desired form of administration with a suitable dosage. The preferred preparations are in a dispensing form that is suitable for oral administration. Such dispensing forms are, for example, tablets, film tablets, coated tablets, capsules, pills, powders, solutions or suspensions or else depot forms.
Corresponding tablets can be obtained by, for example, mixing the active ingredient with known adjuvants, for example inert diluents such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, explosives such as corn starch or alginic acid, binding agents such as starch or gelatin, lubricants such as magnesium stearate or talc, and/or agents for achieving a depot effect, such as carboxylpolymethylene, carboxylmethyl cellulose, cellulose acetate phthalate or polyvinyl acetate. The tablets can also consist of several layers.
Coated tablets can accordingly be produced by coating cores, which are produced analogously to the tablets, with agents that are commonly used in tablet coatings, for example, polyvinylpyrrolidone or shellac, gum arabic, talc, titanium oxide or sugar. In this case, the shells for the coated tablets can also consist of several layers, whereby the adjuvants mentioned above with the tablets can be used.
Solutions or suspensions with the compounds of general formula I according to the invention can contain additional taste-improving agents such as saccharin, cyclamate or sugar, as well as, e.g., flavoring substances such as vanilla or orange extract. In addition, they can contain suspending adjuvants such as sodium carboxymethyl cellulose or preservatives such as p-hydroxybenzoate.
The capsules that contain compounds of general formula I can be produced by, for example, the compound(s) of general formula (I) being mixed with an inert vehicle such as lactose or sorbitol and encapsulated in gelatin capsules.
The prodrugs according to the invention can be synthesized according to the following examples, whereby the latter are used for a more detailed explanation without limiting the invention.
General Synthesis Instructions Variant 1 Reaction with Disulfonic Acid Chlorides A disulfonic acid chloride of general formula S02-X-SO2Cl is dissolved under a cover gas in a base, such as, e.g., pyridine. The corresponding amount of a drug substance is added to the solution. The reaction mixture is stirred until the reaction is completed. Then, the reaction mixture is stirred into a concentrated NH3 solution. The precipitate is filtered off, washed with water and dried. The residue is extracted with an organic solvent, such as, e,g., ethyl acetate, the organic phase is washed, and it is dried with a desiccant such as, e.g., MgSO4. After filtration, it is concentrated by evaporation and chromatographed on silica gel.
Corresponding sulfamoyl sulfonates are obtained.
Variant 2 Reaction with Sulfamoyl Sulfonic Acid Halides A drug substance, as defined above, is dissolved under a cover gas in a base, such as, e.g., pyridine, and an inert solvent, such as, e.g., chloroform. While being cooled, the corresponding amount of a sulfamoyl sulfonic acid halide of general formula SO2Hal is added to the solution. The reaction mixture is stirred until the reaction is completed. Then, water is added, and it is optionally acidified with an acid, such as, e.g., 10%
HCI. It is extracted with an organic solvent, such as, e,g., ethyl acetate, the organic phase is washed, and it is dried with a desiccant, such as, e.g., MgSO4. After filtration, it is concentrated by evaporation and chromatographed on silica gel. Corresponding sulfamoyl sulfonates are obtained.
The corresponding sulfamoyl sulfonic acid halides or disulfonic acid chlorides are commercially available or can be produced by methods that are known to one skilled in the art.
Synthesis Examples Example 1 3 -tert-Butyldimethylsilyloxyestra-1 3 5(10)-trien-17(i-y13'-sulfamoylphenyl Sulfonate 1.9 g of 1,3-benzenedisulfonyl chloride is dissolved under argon in 5 ml of pyridine.
Then, 1.0 g of 3-tert=butyldimethylsilyloxyestra-1,3,5(10)-trien-17(3-ol is added. After 2 hours, the reaction mixture is stirred into 25 ml of a concentrated ammonia solution. After 10 minutes, it is suctioned off, washed with water and dried. The residue is chromatographically purified on silica gel. 3-tert-Butyldimethylsilyloxyestra-1,3,5(10)-trien-17(3-yl 3'-sulfamoylphenyl sulfonate is obtained.
'H-NMR (DMSO-D6): 0.14 (s, 6 H, SiMe), 0.77 (s, 3 H, 18-Me), 0.93 (s, 9 H, t.-Bu), 4.43 (t, 1 H, 17-H), 7.68 (s, 2 H, NHZ).
Example 2 3 -Hydroxyestra-1 3 5(10)-trien-l7R-yl 3'-sulfamoylphenyl Sulfonate 300 mg of 3-tert-butyldimethylsilyloxyestra-1,3,5(10)-trien-17(3-y13'-sulfamoylphenyl sulfonate is dissolved in 20 ml of THF. While being stirred, 200 mg of tetrabutyl ammonium fluoride is added at room temperature. After 1 hour, 20 ml of water is stirred in. The substance is extracted with ethyl acetate. The organic phase is washed with saturated NaCI solution, dried on MgSOa, filtered, concentrated by evaporation and chromatographed on silica gel. 3-Hydroxyestra-1,3,5(10)-trien-17(3-y13'-sulfamoylphenyl sulfonate is obtained.
1H-NMR (DMSO-d6): 0.76 (s, 3 H, 18-Me), 4.43 (t, 1 H, 17-H), 7.68 (s, 2 H, NH2), 8.98 (s, 1H, 3-OH).
Example 3 3 -Oxo-7a-methylestra-4-en-17 D-y13'-sulfamoylphenyl Sulfonate 1.9 g of 1,3-benzenedisulfonyl chloride is dissolved under argon in 5 ml of pyridine.
Then, 1.0 g of MENT is added. After 2 hours, the reaction mixture is stirred into 25 ml of concentrated ammonia solution. After 10 minutes; it is suctioned off, washed with water and dried. The residue is chromatographically purified on silica gel. 3-Oxo-7a-methylestr-4-en-17(3-yl 3'-sulfamoylphenyl sulfonate is obtained.
'H-NMR (DMSO-D6): 0.66 (d, 3 H, 7-Me), 4.38 (t, 1 H, 17-H), 5.69 (s; 1 H, 4-H), 7.67 (s, 2 H, NH2), 7.83 - 8.28 (m, 4 H, H-Ar).
Example 4 3-Oxo-androst-4-en-17p-yl 3'-sulfamoylphenyl Sulfonate Variant 1 2.0 g of 1,3-benzenedisulfonyl chloride is dissolved under argon in 5.5 ml of pyridine.
Then, 1.0 g of testosterone is added. After 2 hours, the reaction mixture is stirred into 25 ml of concentrated ammonia solution. After 10 minutes, it is suctioned off, washed with water and dried. The residue is chromatographically purified on silica gel. 3-Oxo-androst-4-en-17R-y13'-sulfamoylphenyl sulfonate is obtained.
Variant 2 1.0 g of testosterone is dissolved under argon in 5.5 ml of pyridine. Then, 1.8 g of 3-aminosulfonylphenylsulfonyl chloride is added. After 2 hours, the reaction mixture is stirred into 25 ml of water and acidified with 10% HCI. After 10 minutes, it is suctioned off, washed with water and dried. The residue is chromatographically purified on silica gel. 3-Oxo-androst-4-en-17(3-yl 3'-sulfamoylphenyl sulfonate is obtained.
1H-N1VIR (DMSO-D6): 0.78 (s, 3 H, 18-Me), 1.11 (s, 3 H, 19-Me), 4.34 (t, 1 H, H), 5.60 (s, 1 H, 4-H), 7.67 (s, 2 H, NH2), 7.83 - 8.28 (m, 4 H, H-Ar).
Example 5 Zidovudine-sulfamoylphenyl Sulfonate 2.0 g of 1,3-benzenedisulfonyl chloride is dissolved under argon in 5.5 ml of pyridine..
Then, 1.0 g of zidovudine is added at 0 C. After 2 hours of stirring at room temperature, the reaction mixture is added to 25 ml of concentrated ammonia solution. After 10 minutes of stirring, it is evaporated to the dry state and extracted with EE. The organic phase is concentrated by evaporation and the residue is chromatographically purified on silica gel.
Zidovudine-sulfamoylphenyl sulfonate is obtained.
1H-NMR (DMSO-D6): 1.17 (s, 3 H, Me), 2.40 (m, 2 H, CH2), 4.00 (m, 1 H, CH), 4.42 (m, 2 H, CH2), 6.09 (m, 1 H, CH), 7.40 (s, 1 H, CH), 7.66 (s, 2 H, NH2), 7.85-8.30 (3 m + s, 5 H, 4-H), 11.35 (s, 1 H, NH).
The "C3_8-cycloalkyl-C1_4-alkanediyl group" means, for example, cycloalkyl-(CH2)-, cycloalkyl-(C2H4)-, cycloalkyl-(C3H6)-, cycloalkyl-(C4Hg)-, or cycloalkyl-(C5H,o)-. In this case, cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.
"C1_4-Alkyl-C3_8-cycloalkanediyl group" is defined as methylcycloalkanediyl, ethyl-cycloalkanediyl, propylcycloalkanediyl, butylcycloalkanediyl, or pentylcycloalkanediyl. In this case, cycloalkanediyl can be cyclopropane-1,3-diyl, cyclobutane-1,4-diyl, cyclopentane-1,5-diyl, cyclohexane-1,6-diyl, cycloheptane-1,7-diyl or cyclooctane-1,8-diyl.
In the context of this invention, the term "halogen atom" is defined as a fluorine, chlorine, bromine or iodine atom, preferably a fluorine, chlorine, or bromine atom.
A pharmaceutical active ingredient that can form a sulfonate via an OH group means, for the purpose of the invention, the following:
Steroids: Estrogens, for example estradiol or estriol, or androgens, for example testosterone, MENT (7 a-methyl-19-nortestosterone), eF-MENT (11 -fluoro-7 a-methyl-l9-nortestosterone), nandrolone, DHT (dihydrotestosterone), or gestagens, for example norethisterone, dienogest or levonorgestrel, or corticoids, for example cortisol Anti-malaria agents: quinine, cinchonidine, hydroxychloroquine, primaquine, mefloquine;
or Nucleosides: consisting of a sugar, such as ribose or deoxyribose, and a base, such as adenine, guanine, cytosine, thymine or uracil, and also zidovudine, brivudine, indinavir, and nelfinavir;
Isoflavonoids: genisteine.
Especially preferred compounds are specified as follows:
1) 3-hydroxyestra-1,3,5(10)-trien-17(3-y13'-sulfamoylphenyl sulfonate, 2) 3-acetoxyestra-1,3,5(10)-trien-17(3-yl 3'- sulfamoylphenyl sulfonate, 3) 3-tert-butyldimethylsilyloxyestra-1,3,5(10)-trien-170-yl 3'-sulfamoylphenyl sulfonate, 4) 3-hydroxyestra-1,3,5(10)-trien-l7R-y14'-sulfamoylphenyl sulfonate, 5) 2-methoxy-3-hydroxyestra-1,3,5(10)-trien-170-yl 3'-sulfamoylphenyl sulfonate, 6) 3,16a-dihydroxyestra-1,3,5(10)-trien-17(3-yl 3'-sulfamoylphenyl sulfonate, 7) 3,170 -dihydroxyestra-1,3,5(10)-trien-16a-y13'-sulfamoylphenyl sulfonate, 8) 3-benzoyloxyestra-1,3,5(10)-trien-170-yl 3'-sulfamoylphenyl sulfonate, 9) quinine-3'-sulfamoylphenyl sulfonate, 10) cinchonidine-3'-sulfamoylphenyl sulfonate, 11) zidovudine-3'-sulfamoylphenyl sulfonate, 12) 3-oxoandrost-4-en-170-yl 3'-sulfamoylphenyl sulfonate, 13) 3-oxoandrostan-17P-yl 3'-sulfamoylphenyl sulfonate, 14) 3-oxo-7a-methylandrost-4-en-170-yl 3'-sulfamoylphenyl sulfonate, 15) 3-oxoestr-4-en-17(3-yl 3'-sulfamoylphenyl sulfonate, and 16) brivudine-3'-sulfamoylphenyl sulfonate.
The therapeutically relevant drug compound is released through hydrolysis from the compounds according to the invention.
In-Vitro Tests:
Carbonic Anhydrase Inhibition Test Principle:
Photometric determination of the inhibition of human carbonic anhydrase I or II with sulfonamides or sulfamates on microtiter plates with the aid of enzymatic conversion of nitrophenyl acetate with a color change from colorless to yellow.
Table 1: IC50 Inhibiting Values of Human Carbonic Anhydrase I
CAII CAI
Inhibitor IC50 (nM) IC50 (nM) Estradiol-3-sulfamat 34 157 10.6 3-Oxoandrost-4-en-17R-yI 120 2300 3'-aminosulfonylphenyl-sulfonat 3-Oxo-7a-methylandrost-4- 120 2300 en-170-yi 3'-aminosulfonyl-hen Isulfonat 3-Hydroxyestra-1,3,5(10)- 81 1700 trien-17p-yl 3'-aminosulfo-n I hen Isulfonat Zidovudinsulfonat 1100 2900 Acetazolamid 61 1200 bekannter CA-Hemmer) 190 Literature: 1) C. Landolfi, M. Marchetti, G. Ciocci, and C. Milanese, Journal of Pharmacological and Toxicological Methods 38, 169-172 (1997).
[Key to Table 1:]
Estradiol-3-sulfamat = Estradiol-3-sulfamate 3-Oxoandrost-4-en-17R-yl 3'-aminosulfamoylphenylsulfonat = 3-Oxoandrost-4-en-170-yl 3'-sulfamoylphenyl sulfonate 3 -Oxo-7a-methylandrost-4-en-17 0-yl 3'-aminosulfamoylphenylsulfonat = 3 -Oxo-7a-methylandrost-4-en-17(3-yl 3'-aminosulfamoylphenyl sulfonate 3-Hydroxyestra-1,3,5(10)-trien-17(3-yl 3'-aminosulfonylphenylsulfonat = 3-Hydroxyestra-1,3,5(10)-trien-l7R-yl 3'-aminosulfonylphenyl sulfonate Zidovudinsulfonat = Zidovudine Sulfonate Acetazolamid (bekannter CA-Hemmer) = Acetazolamide (Known CA Inhibitor) It was found that the sulfamoyl sulfonate prodrugs according to the invention surprisingly readily inhibit the carbonic anhydrase II. A concentration of the prodrugs, according to the invention, in the erythrocytes can be deduced from this.
Physicochemical Data Solubility in Water a) Kinetic Measurement:
The compounds according to the invention were measured as 10 mmol DMSO
solution in a 0.01 M phosphate buffer solution at pH 7.4 and 25 C with nephelometry and turbidity.
While in a turbid state, the solution to be tested was added drop by drop to the buffer solution until a precipitate settled.
The precipitate was detected in a dilution series (compounds in a phosphate buffer solution according to the invention) by nephelometry.
b.) Thermodynamic Measurement:
The compounds in solid form according to the invention were added to an excess of an aqueous buffer system of various pH values. It was stirred 24 hours at 25 C. After centrifuging, the solution was examined with HPLC (HPLC: column: Xterra MS C18 2.5 m, 30 x 4.6 mm). Two standard gradient systems were used based on the compounds to be measured:
Acidic gradient: A: water/0.01 % trifluoroacetic acid, B: acetonitrile/0. 0 1 %
trifluoroacetic acid - 0 min 5% B, 0-3 min 65% B, 3-5 min 65% B, 5-6 min 5% B
Alkaline gradient: A: water/0.025% ammonia, B: acetonitrile/0.025% ammonia - 0 min 20% B, 0-3 min 80% B, 3-5 min 80% B, 5-6 min 20% B.
Table 2: Water Solubility Substance Solubility in Water Estradiol-3-sulfamate 0.15 mg/100 ml Testosterone Propionate Insoluble 3-Hydroxyestra-1,3,5(10)-trien-170-y13'- 3 mg/1 sulfamoylphenyl Sulfonate 3-Oxoandrost-4-en-170-yl 3'-sulfamoyl- 5 mg/l phenyl Sulfonate 3-Oxo-7a-methylandrost-4-en-17(3-yl 3'- About 6 mg/1 sulfamoylphenyl Sulfonate The compounds according to the invention show a higher solubility when compared to sulfamate- and carboxylic acid ester prodrugs, which allows for better absorption in the intestine.
Hydrolysis The compounds according to the invention were measured as a DMSO solution in an aqueous buffer of various pH values at 37 C.
The quantification took place through HPLC (HPLC column: Xterra MS C18 2.5 m 4.6 x 30mm). Based on the test substances to be measured, the following gradient system was used for the HPLC:
Acidic gradient: A: water/0.01 % trifluoroacetic acid, B: acetonitrile/0. 0 1 %
trifluoroacetic acid - 0 min 5% B, 0-3 min 65% B, 3=5 min 65% B, 5-6 min 5% B
Alkaline gradient: A: water/0.025% ammonia, B: acetonitrile/0.025% ammonia - 0 min 20% B, 0-3 min 80% B, 3-5 min 80% B, 5-6 min 20% B. The quantification took' place after 1 and 2 hours and after 24 hours.
Stability in Simulated Gastric Juice:
Solutions of the compounds according to the invention were incubated at 37 C
in simulated gastric juice (aqueous NaCI solution with pepsin, pH- 1.2).
The quantification took place through HPLC (HPLC-column: Xterra MS C18 2.5 m 4.6 x 30mm) using the gradient system:
A: water/0.01 % trifluoroacetic acid, B: acetonitrile/0.01 % trifluoroacetic acid - 0 min 5% B, 0-3 min 65% B, 3-5 min 65% B, 5-6 min 5% B.
The quantification took place after 0.5, 1, 1.5 and 2 hours.
Table 3: Hydrolysis/Stability in Gastric Juice Decomposition in %
pH =1, 37 C pH = 7.4, 37 C
Substance 30 min 1 h 2 h 24 h 1 h 2h. 24 h 3-Hydroxyestra-1,3,5 4 7 14 80 6 13 84 (10)-trien-17(3-yl3'- (pH=1.2) sulfamoyl-phenyl sulfonate 3-Oxoandrost-4-en- 3 6 11 78 6 12 75 17 (3-y13'-sulfamoyl- (pH=1.2) phenyl sulfonate 3-Oxo-7a-methyl- 6 11 71 6 11 70 androst-4-en-17p-yl 3'-sulfamoylphenyl sulfonate 3-Oxoandrost-4-en- 0 0 0 0 0 0 0 17(3-yl n-propionate Carboxylic acid esters are relatively stable in gastric juice (pH - 1) and in the intestine (pH - 7.4), but are cleaved when passing through the intestine by esterases that exist there. During passage through the stomach, however, the stable prodrug remains almost complete.
The cleavage of the carboxylic acid ester thus takes place when passing through the intestine and in the liver.
No enzymes (esterases) are known for sulfonic acid ester. It was therefore surprising that the sulfonates are still cleaved, whereby a simple hydrolysis takes place. Although a slow hydrolysis already takes place in the gastric juice and when the pH = 7.4, the sulfonates have adequate stability to pass through the stomach and the intestine. An esterase cleavage does not take place in the intestine wall. The first-pass effect in the liver is avoided since the sulfonates are bonded with the sulfonamide group to the erythrocytes.
The compounds of general formula (I) according to the invention can, as a function of the meaning of "drug," be used for the treatment and/or prophylaxis of various clinical pictures. For example, the compounds of general formula (I) can be used if the "drug" is a steroid, such as androgen or estrogen, in hormone replacement therapy (HRT) in women and men, or in the treatment of hormonally-induced diseases in men (prostrate cancer, breast cancer, hypogonadism) and in women (endometriosis, breast cancer). In addition, the compounds of general formula (I) according to the invention, in which "drug,"
for example, stands for an androgen or estrogen, can he used for birth control in men and women.
The use of additional active ingredients mentioned for "drug," such as quinine, cinchonidine, hydroxychloroquine, primaquine or mefloquine, relates to the treatment of malaria.
Compounds of general formula (I) according to the invention, in which "drug"
means a cortisol derivative, can be used for the treatment and prophylaxis of inflammatory and/or allergic diseases that are influenced by immunosuppressive agents and/or antiproliferative agents.
Prodrugs according to the invention, in which "drug" means a nucleoside (zidovudine, brivudine, indinavir, nelfinavir), can be used for the treatment of viral diseases (herpes, HIV).
In addition, subjects of the invention are the pharmaceutical compositions that contain the compounds of general formula (I) according to the invention and optionally additional active ingredients, for example gestagens (norethisterone, dienogest, drospirenone, levonorgestrel), antigestagens (mifepristone, onapristone) and/or progesterone receptor modulators (mesoprogestins, such as asoprisnil).
These pharmaceutical compositions and pharmaceutical agents are preferably administered orally. In addition to the usual vehicles and/or diluents, they contain at least one compound of general formula I.
Dosage The prodrugs according to the invention can be administered orally.
Generally, satisfactory results are to be expected both for the treatment and/or prophylaxis of the above-mentioned indications or for birth control if the dosage is carried out in such a way that after the administration of the prodrugs, an amount of the corresponding active ingredient ("drug") is released that corresponds to the highest pharmaceutically used maximum dose of the respective "drug" substance.
The pharmaceutical agents of the invention are produced in a known way with the usual solid or liquid vehicles or diluents and the commonly used pharmaceutical-technical adjuvants corresponding to the desired form of administration with a suitable dosage. The preferred preparations are in a dispensing form that is suitable for oral administration. Such dispensing forms are, for example, tablets, film tablets, coated tablets, capsules, pills, powders, solutions or suspensions or else depot forms.
Corresponding tablets can be obtained by, for example, mixing the active ingredient with known adjuvants, for example inert diluents such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, explosives such as corn starch or alginic acid, binding agents such as starch or gelatin, lubricants such as magnesium stearate or talc, and/or agents for achieving a depot effect, such as carboxylpolymethylene, carboxylmethyl cellulose, cellulose acetate phthalate or polyvinyl acetate. The tablets can also consist of several layers.
Coated tablets can accordingly be produced by coating cores, which are produced analogously to the tablets, with agents that are commonly used in tablet coatings, for example, polyvinylpyrrolidone or shellac, gum arabic, talc, titanium oxide or sugar. In this case, the shells for the coated tablets can also consist of several layers, whereby the adjuvants mentioned above with the tablets can be used.
Solutions or suspensions with the compounds of general formula I according to the invention can contain additional taste-improving agents such as saccharin, cyclamate or sugar, as well as, e.g., flavoring substances such as vanilla or orange extract. In addition, they can contain suspending adjuvants such as sodium carboxymethyl cellulose or preservatives such as p-hydroxybenzoate.
The capsules that contain compounds of general formula I can be produced by, for example, the compound(s) of general formula (I) being mixed with an inert vehicle such as lactose or sorbitol and encapsulated in gelatin capsules.
The prodrugs according to the invention can be synthesized according to the following examples, whereby the latter are used for a more detailed explanation without limiting the invention.
General Synthesis Instructions Variant 1 Reaction with Disulfonic Acid Chlorides A disulfonic acid chloride of general formula S02-X-SO2Cl is dissolved under a cover gas in a base, such as, e.g., pyridine. The corresponding amount of a drug substance is added to the solution. The reaction mixture is stirred until the reaction is completed. Then, the reaction mixture is stirred into a concentrated NH3 solution. The precipitate is filtered off, washed with water and dried. The residue is extracted with an organic solvent, such as, e,g., ethyl acetate, the organic phase is washed, and it is dried with a desiccant such as, e.g., MgSO4. After filtration, it is concentrated by evaporation and chromatographed on silica gel.
Corresponding sulfamoyl sulfonates are obtained.
Variant 2 Reaction with Sulfamoyl Sulfonic Acid Halides A drug substance, as defined above, is dissolved under a cover gas in a base, such as, e.g., pyridine, and an inert solvent, such as, e.g., chloroform. While being cooled, the corresponding amount of a sulfamoyl sulfonic acid halide of general formula SO2Hal is added to the solution. The reaction mixture is stirred until the reaction is completed. Then, water is added, and it is optionally acidified with an acid, such as, e.g., 10%
HCI. It is extracted with an organic solvent, such as, e,g., ethyl acetate, the organic phase is washed, and it is dried with a desiccant, such as, e.g., MgSO4. After filtration, it is concentrated by evaporation and chromatographed on silica gel. Corresponding sulfamoyl sulfonates are obtained.
The corresponding sulfamoyl sulfonic acid halides or disulfonic acid chlorides are commercially available or can be produced by methods that are known to one skilled in the art.
Synthesis Examples Example 1 3 -tert-Butyldimethylsilyloxyestra-1 3 5(10)-trien-17(i-y13'-sulfamoylphenyl Sulfonate 1.9 g of 1,3-benzenedisulfonyl chloride is dissolved under argon in 5 ml of pyridine.
Then, 1.0 g of 3-tert=butyldimethylsilyloxyestra-1,3,5(10)-trien-17(3-ol is added. After 2 hours, the reaction mixture is stirred into 25 ml of a concentrated ammonia solution. After 10 minutes, it is suctioned off, washed with water and dried. The residue is chromatographically purified on silica gel. 3-tert-Butyldimethylsilyloxyestra-1,3,5(10)-trien-17(3-yl 3'-sulfamoylphenyl sulfonate is obtained.
'H-NMR (DMSO-D6): 0.14 (s, 6 H, SiMe), 0.77 (s, 3 H, 18-Me), 0.93 (s, 9 H, t.-Bu), 4.43 (t, 1 H, 17-H), 7.68 (s, 2 H, NHZ).
Example 2 3 -Hydroxyestra-1 3 5(10)-trien-l7R-yl 3'-sulfamoylphenyl Sulfonate 300 mg of 3-tert-butyldimethylsilyloxyestra-1,3,5(10)-trien-17(3-y13'-sulfamoylphenyl sulfonate is dissolved in 20 ml of THF. While being stirred, 200 mg of tetrabutyl ammonium fluoride is added at room temperature. After 1 hour, 20 ml of water is stirred in. The substance is extracted with ethyl acetate. The organic phase is washed with saturated NaCI solution, dried on MgSOa, filtered, concentrated by evaporation and chromatographed on silica gel. 3-Hydroxyestra-1,3,5(10)-trien-17(3-y13'-sulfamoylphenyl sulfonate is obtained.
1H-NMR (DMSO-d6): 0.76 (s, 3 H, 18-Me), 4.43 (t, 1 H, 17-H), 7.68 (s, 2 H, NH2), 8.98 (s, 1H, 3-OH).
Example 3 3 -Oxo-7a-methylestra-4-en-17 D-y13'-sulfamoylphenyl Sulfonate 1.9 g of 1,3-benzenedisulfonyl chloride is dissolved under argon in 5 ml of pyridine.
Then, 1.0 g of MENT is added. After 2 hours, the reaction mixture is stirred into 25 ml of concentrated ammonia solution. After 10 minutes; it is suctioned off, washed with water and dried. The residue is chromatographically purified on silica gel. 3-Oxo-7a-methylestr-4-en-17(3-yl 3'-sulfamoylphenyl sulfonate is obtained.
'H-NMR (DMSO-D6): 0.66 (d, 3 H, 7-Me), 4.38 (t, 1 H, 17-H), 5.69 (s; 1 H, 4-H), 7.67 (s, 2 H, NH2), 7.83 - 8.28 (m, 4 H, H-Ar).
Example 4 3-Oxo-androst-4-en-17p-yl 3'-sulfamoylphenyl Sulfonate Variant 1 2.0 g of 1,3-benzenedisulfonyl chloride is dissolved under argon in 5.5 ml of pyridine.
Then, 1.0 g of testosterone is added. After 2 hours, the reaction mixture is stirred into 25 ml of concentrated ammonia solution. After 10 minutes, it is suctioned off, washed with water and dried. The residue is chromatographically purified on silica gel. 3-Oxo-androst-4-en-17R-y13'-sulfamoylphenyl sulfonate is obtained.
Variant 2 1.0 g of testosterone is dissolved under argon in 5.5 ml of pyridine. Then, 1.8 g of 3-aminosulfonylphenylsulfonyl chloride is added. After 2 hours, the reaction mixture is stirred into 25 ml of water and acidified with 10% HCI. After 10 minutes, it is suctioned off, washed with water and dried. The residue is chromatographically purified on silica gel. 3-Oxo-androst-4-en-17(3-yl 3'-sulfamoylphenyl sulfonate is obtained.
1H-N1VIR (DMSO-D6): 0.78 (s, 3 H, 18-Me), 1.11 (s, 3 H, 19-Me), 4.34 (t, 1 H, H), 5.60 (s, 1 H, 4-H), 7.67 (s, 2 H, NH2), 7.83 - 8.28 (m, 4 H, H-Ar).
Example 5 Zidovudine-sulfamoylphenyl Sulfonate 2.0 g of 1,3-benzenedisulfonyl chloride is dissolved under argon in 5.5 ml of pyridine..
Then, 1.0 g of zidovudine is added at 0 C. After 2 hours of stirring at room temperature, the reaction mixture is added to 25 ml of concentrated ammonia solution. After 10 minutes of stirring, it is evaporated to the dry state and extracted with EE. The organic phase is concentrated by evaporation and the residue is chromatographically purified on silica gel.
Zidovudine-sulfamoylphenyl sulfonate is obtained.
1H-NMR (DMSO-D6): 1.17 (s, 3 H, Me), 2.40 (m, 2 H, CH2), 4.00 (m, 1 H, CH), 4.42 (m, 2 H, CH2), 6.09 (m, 1 H, CH), 7.40 (s, 1 H, CH), 7.66 (s, 2 H, NH2), 7.85-8.30 (3 m + s, 5 H, 4-H), 11.35 (s, 1 H, NH).
Example 6 Cinchonidine-sulfamoylphenyl Sulfonate 2.0 g of 1,3-benzenedisulfonyl chloride is dissolved under argon in 5.5 ml of pyridine.
Then, 1.0 g of cinchonidine is added at 0 C. After 2 hours of stirring at room temperature, the reaction mixture is added to 25 ml of concentrated ammonia solution. After 10 minutes of stirring, it is evaporated to the dry state and extracted with EE. The organic phase is concentrated by evaporation, and the residue is chromatographically purified on silica gel.
Cinchonidine-sulfamoylphenyl sulfonate is obtained.
'H-NMR (DMSO-D6): 4.99 (m, 2 H, CH=CH2), 5.94 (m, 1 H, CH=CH2), 7.58 (s, 2 H, NH2).
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent.
The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.
In the foregoing and in the following examples, all temperatures are set forth uncorrected in degrees Celsius, and all parts and percentages are by weight, unless otherwise indicated.
The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.
From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention and, without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions. -
Then, 1.0 g of cinchonidine is added at 0 C. After 2 hours of stirring at room temperature, the reaction mixture is added to 25 ml of concentrated ammonia solution. After 10 minutes of stirring, it is evaporated to the dry state and extracted with EE. The organic phase is concentrated by evaporation, and the residue is chromatographically purified on silica gel.
Cinchonidine-sulfamoylphenyl sulfonate is obtained.
'H-NMR (DMSO-D6): 4.99 (m, 2 H, CH=CH2), 5.94 (m, 1 H, CH=CH2), 7.58 (s, 2 H, NH2).
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent.
The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.
In the foregoing and in the following examples, all temperatures are set forth uncorrected in degrees Celsius, and all parts and percentages are by weight, unless otherwise indicated.
The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.
From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention and, without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions. -
Claims (21)
1. Sulphamoylsulphonate prodrugs of the general formula I
in which X is an optionally substituted C1-C12-alkanediyl group, a C p F2p group where p = 1-5, a mono- or bicyclic, optionally halogen-, hydroxyl- or nitrile-substituted C3-8-cycloalkanediyl group, a mono- to tricyclic, optionally halogen-, hydroxyl-, nitrile- and alkyl-substituted C6-C15-arylene group, a heteroalkanediyl group having 1 to 6 carbon atoms which in place of the carbon contains one or more, identical or different heteroatoms, also a C1-4-alkanediylaryl, a C1-4-alkanediyl-C3-6-cycloalkyl or C3-8-cycloalkanediyl-C1-4-alkyl group, and Drug represents a pharmaceutical active compound which can form a sulphonate group via an OH
group, such as steroids, antimalarial agents, nucleosides, isoflavonoids, which can optionally be substituted.
in which X is an optionally substituted C1-C12-alkanediyl group, a C p F2p group where p = 1-5, a mono- or bicyclic, optionally halogen-, hydroxyl- or nitrile-substituted C3-8-cycloalkanediyl group, a mono- to tricyclic, optionally halogen-, hydroxyl-, nitrile- and alkyl-substituted C6-C15-arylene group, a heteroalkanediyl group having 1 to 6 carbon atoms which in place of the carbon contains one or more, identical or different heteroatoms, also a C1-4-alkanediylaryl, a C1-4-alkanediyl-C3-6-cycloalkyl or C3-8-cycloalkanediyl-C1-4-alkyl group, and Drug represents a pharmaceutical active compound which can form a sulphonate group via an OH
group, such as steroids, antimalarial agents, nucleosides, isoflavonoids, which can optionally be substituted.
2. Sulphamoylsulphonate prodrugs according to Claim 1, wherein Drug represents steroids such as oestrogens, for example oestradiol or oestriol, or androgens, for example testosterone, MENT
(7.alpha.-methyl-19-nor-testosterone), eF-MENT (11-fluoro-7.alpha.-methyl-19-nortestosterone), nandrolone, DHT (dihydro-testosterone), or gestagens, for example norethisterone, dienogest or levonorgestrel, or corticoids, for example cortisol, or anti-malarial agents, for example quinine, chinchonidine, hydroxychloroquine, primaquine, mefloquine, or nucleosides consisting of a sugar such as ribose or deoxyribose and of a base such as adenine, guanine, cytosine, thymine or uracil, furthermore zidovudine, brivudine, indinavir, nelfinavir or isoflavonoids, for example genistein.
(7.alpha.-methyl-19-nor-testosterone), eF-MENT (11-fluoro-7.alpha.-methyl-19-nortestosterone), nandrolone, DHT (dihydro-testosterone), or gestagens, for example norethisterone, dienogest or levonorgestrel, or corticoids, for example cortisol, or anti-malarial agents, for example quinine, chinchonidine, hydroxychloroquine, primaquine, mefloquine, or nucleosides consisting of a sugar such as ribose or deoxyribose and of a base such as adenine, guanine, cytosine, thymine or uracil, furthermore zidovudine, brivudine, indinavir, nelfinavir or isoflavonoids, for example genistein.
3. Sulphamoylsulphonate prodrugs according to Claim 1, wherein X is an arylene group.
4. Sulphamoylsulphonate prodrugs according to Claim 3, wherein X is an unsubstituted or chlorine-substituted phenylene, pyridylene or thiophenylene radical.
5. Sulphamoylsulphonate prodrugs according to Claim 3 or 4, namely 1) 3-hydroxyoestra-1,3,5(10)-trien-17.beta.-yl 3'-sulphamoylphenylsulphonate, 2) 3-acetoxyoestra-1,3,5(10)-trien-17.beta.-yl 3'-sulphamoylphenylsulphonate, 3) 3-tert-butyldimethylsilyloxyoestra-1,3,5(10)-trien-17.beta.-yl 3'-sulphamoylphenylsulphonate, 4) 3-hydroxyoestra-1,3,5(10)-trien-17.beta.-yl 4'-sulphamoylphenylsulphonate, 5) 2-methoxy-3-hydroxyoestra-1,3,5(10)-trien-17.beta.-yl 3'-sulphamoylphenylsulphonate,
6) 3,16.alpha.-dihydroxyoestra-1,3,5(10)-trien-17.beta.-yl 3'-sulphamoylphenylsulphonate,
7) 3,17.beta.-dihydroxyoestra-1,3,5(10)-trien-16.alpha.-yl 3'-sulphamoylphenylsulphonate,
8) 3-benzoyloxyoestra-1,3,5(10)-trien-17.beta.-yl 3'-sulphamoylphenylsulphonate,
9) quinine-3'-sulphamoylphenylsulphonate,
10)chinchonidine-3'-sulphamoylphenylsulphonate,
11)zidovudine-3'-sulphamoylphenylsulphonate,
12)3-oxoandrost-4-en-17.beta.-yl 3'-sulphamoylphenyl-sulphonate,
13)3-oxoandrostan-17.beta.-yl 3'-sulphamoylphenyl-sulphonate,
14)3-oxo-7.alpha.-methylandrost-4-en-17.beta.-yl 3'-sulph-amoylphenylsulphonate,
15)3-oxooestr-4-en-17.beta.-yl 3'-sulphamoylphenyl-sulphonate,
16)Brivudine-3'-sulphamoylphenylsulphonate.
6. Compounds according to any one of Claims 1, 3 or 4, wherein the active compound is an antimalarial agent such as arteether, artemether, artesunate, chloroquine, pamaquine, primaquine, pyrethamine, mefloquine, proguanil, chinchonidine, cinchonine, hydroxychloroquine, pamaquine, primaquine, pyrimethamine, quinine or a quinine derivative, such as quinine bisulphate, quinine carbonate, quinine dihydrobromide, quinine dihydrochloride, quinine ethylcarbonate, quinine formate, quinine gluconate, quinine hydroiodide, quinine hydrochloride, quinine salicylate or quinine sulphate.
7. Use of the compounds according to Claim 6 for the prevention of a parasitic attack on erythrocytes.
8. Compounds according to any one of Claims 1-7, wherein the therapeutically desired action takes place by release, in particular hydrolytic cleavage, of the active compound contained in the prodrug or its metabolites.
9. Pharmaceutical composition comprising at least one compound of the general formula I according to any one of Claims 1 to 5 and optionally at least one further active compound together with pharmaceutically tolerable excipients and/or vehicles.
10. Pharmaceutical composition according to Claim 9, wherein the further active compound is a steroidal compound.
11. Pharmaceutical composition according to Claim 10, wherein the further steroidal compound is a gestagen, anti-gestagen or a progesterone receptor modulator.
12. Pharmaceutical composition according to Claim 11, wherein the gestagens contained are norethisterone, dienogest, drospirenone, levo-norgestrel, the anti-gestagens mifepristone, onapristone and progesterone receptor modulators, for example mesoprogestins such as asoprisnil.
13. Use of compounds according to any one of Claims 1 to 8 in the manufacture of a medicament.
14. Use according to Claim 13 in the manufacture of a medicament for hormone replacement therapy.
15. Use of compounds according to Claims 1-8 for female fertility control.
16. Use according to Claim 13 in the manufacture of a medicament for the therapy and/or prophylaxis of hormonally caused diseases in men and women.
6. Compounds according to any one of Claims 1, 3 or 4, wherein the active compound is an antimalarial agent such as arteether, artemether, artesunate, chloroquine, pamaquine, primaquine, pyrethamine, mefloquine, proguanil, chinchonidine, cinchonine, hydroxychloroquine, pamaquine, primaquine, pyrimethamine, quinine or a quinine derivative, such as quinine bisulphate, quinine carbonate, quinine dihydrobromide, quinine dihydrochloride, quinine ethylcarbonate, quinine formate, quinine gluconate, quinine hydroiodide, quinine hydrochloride, quinine salicylate or quinine sulphate.
7. Use of the compounds according to Claim 6 for the prevention of a parasitic attack on erythrocytes.
8. Compounds according to any one of Claims 1-7, wherein the therapeutically desired action takes place by release, in particular hydrolytic cleavage, of the active compound contained in the prodrug or its metabolites.
9. Pharmaceutical composition comprising at least one compound of the general formula I according to any one of Claims 1 to 5 and optionally at least one further active compound together with pharmaceutically tolerable excipients and/or vehicles.
10. Pharmaceutical composition according to Claim 9, wherein the further active compound is a steroidal compound.
11. Pharmaceutical composition according to Claim 10, wherein the further steroidal compound is a gestagen, anti-gestagen or a progesterone receptor modulator.
12. Pharmaceutical composition according to Claim 11, wherein the gestagens contained are norethisterone, dienogest, drospirenone, levo-norgestrel, the anti-gestagens mifepristone, onapristone and progesterone receptor modulators, for example mesoprogestins such as asoprisnil.
13. Use of compounds according to any one of Claims 1 to 8 in the manufacture of a medicament.
14. Use according to Claim 13 in the manufacture of a medicament for hormone replacement therapy.
15. Use of compounds according to Claims 1-8 for female fertility control.
16. Use according to Claim 13 in the manufacture of a medicament for the therapy and/or prophylaxis of hormonally caused diseases in men and women.
17. Use according to Claim 13 in the manufacture of a medicament for the therapy and prophylaxis of endometriosis, mammary carcinomas, carcinomas of the prostate or hypogonadism.
18. Use according to Claim 13 in the manufacture of a medicament for the therapy and/or prophylaxis of diseases which can be positively influenced by the inhibition of the carboanhydrase activity.
19. Use according to Claim 13 in the manufacture of a medicament for the therapy and/or prophylaxis of inflammatory and/or allergic diseases.
20. Process for the preparation of the sulphamoylsulphonate prodrugs of the general formula (I) according to Claim 1 by reaction of an appropriate Drug according to Claims 1 and 2 with a disulphonyl chloride ClSO2-X-SO2Cl in the presence of a base and subsequent treatment with ammonia or by reaction of the appropriate Drug according to Claims 1 and 2 with a sulphamoylsulphonyl halide NH2SO2-X-SO2Cl in the presence of a base.
21. Process according to Claim 20, wherein the base is pyridine.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE102005057408A DE102005057408A1 (en) | 2005-11-30 | 2005-11-30 | New sulfamoylsulfonate prodrugs e.g. useful for protecting red blood cells from attack by parasites or for hormone replacement therapy, female fertility control or treating hormone-associated diseases |
| DE102005057408.4 | 2005-11-30 | ||
| PCT/EP2006/011726 WO2007062874A2 (en) | 2005-11-30 | 2006-11-27 | Sulfamoyl sulfonate prodrugs |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2632272A1 true CA2632272A1 (en) | 2007-06-07 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002632272A Abandoned CA2632272A1 (en) | 2005-11-30 | 2006-11-27 | Sulfamoyl sulfonate prodrugs |
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| EP (1) | EP1957513A2 (en) |
| JP (1) | JP2009517424A (en) |
| KR (1) | KR20080072956A (en) |
| CN (1) | CN101316858A (en) |
| AU (1) | AU2006319380A1 (en) |
| BR (1) | BRPI0619253A2 (en) |
| CA (1) | CA2632272A1 (en) |
| CR (1) | CR10003A (en) |
| DE (1) | DE102005057408A1 (en) |
| EA (1) | EA200801306A1 (en) |
| EC (1) | ECSP088489A (en) |
| IL (1) | IL191570A0 (en) |
| NO (1) | NO20082915L (en) |
| WO (1) | WO2007062874A2 (en) |
| ZA (1) | ZA200805659B (en) |
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| US8293783B2 (en) * | 2009-03-24 | 2012-10-23 | National University Of Singapore | Use of artemisinin derivatives for the treatment of asthma and chronic obstructive pulmonary disease (COPD) |
| CN101987104A (en) * | 2009-08-05 | 2011-03-23 | 天津金耀集团有限公司 | Ophthalmic composition of heteroaryl sulfamoyl carboxylic ester carbonic anhydrase inhibitor |
| CN101987101A (en) * | 2009-08-05 | 2011-03-23 | 天津金耀集团有限公司 | Anti-inflammatory eye composition with glucocorticoid aromatic sulfamoyl sulfonic acid ester as active ingredient |
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| DE10027887A1 (en) * | 2000-05-31 | 2001-12-13 | Jenapharm Gmbh | Compounds with a sulfonamide group and pharmaceutical compositions containing these compounds |
| DE102004025966A1 (en) * | 2004-05-21 | 2005-12-15 | Schering Ag | Estradiol prodrugs |
| DE102004025986A1 (en) * | 2004-05-21 | 2005-12-15 | Schering Ag | Steroid prodrugs with androgenic effects |
| DE102004025985A1 (en) * | 2004-05-21 | 2005-12-15 | Schering Ag | Estriol and estetrol prodrugs |
-
2005
- 2005-11-30 DE DE102005057408A patent/DE102005057408A1/en not_active Ceased
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2006
- 2006-11-27 JP JP2008542678A patent/JP2009517424A/en active Pending
- 2006-11-27 EP EP06829354A patent/EP1957513A2/en not_active Withdrawn
- 2006-11-27 CN CNA2006800449086A patent/CN101316858A/en active Pending
- 2006-11-27 WO PCT/EP2006/011726 patent/WO2007062874A2/en active Application Filing
- 2006-11-27 CA CA002632272A patent/CA2632272A1/en not_active Abandoned
- 2006-11-27 AU AU2006319380A patent/AU2006319380A1/en not_active Abandoned
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- 2006-11-27 BR BRPI0619253-0A patent/BRPI0619253A2/en not_active Application Discontinuation
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- 2008-05-20 IL IL191570A patent/IL191570A0/en unknown
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| KR20080072956A (en) | 2008-08-07 |
| AU2006319380A1 (en) | 2007-06-07 |
| DE102005057408A1 (en) | 2007-05-31 |
| WO2007062874A3 (en) | 2007-07-12 |
| ZA200805659B (en) | 2009-10-28 |
| CN101316858A (en) | 2008-12-03 |
| JP2009517424A (en) | 2009-04-30 |
| EP1957513A2 (en) | 2008-08-20 |
| WO2007062874B1 (en) | 2007-09-27 |
| CR10003A (en) | 2008-08-21 |
| WO2007062874A2 (en) | 2007-06-07 |
| IL191570A0 (en) | 2008-12-29 |
| BRPI0619253A2 (en) | 2011-09-27 |
| ECSP088489A (en) | 2008-06-30 |
| EA200801306A1 (en) | 2008-10-30 |
| NO20082915L (en) | 2008-06-27 |
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